Association Testing in a Linked Region Using Large Pedigrees

Abstract

This report describes computer implementation of a scheme for joint linkage and association analysis. The model implemented in the computer package Mendel estimates both recombination and linkage-disequilibrium parameters and conducts likelihood-ratio tests for (1) linkage alone, (2) linkage and association simultaneously, and (3) association in the presence of linkage. Application of the method to data from Finnish pedigrees with familial combined hyperlipidemia illustrates its potential for identification of associated SNP haplotypes in the presence of linkage. For the test results to be valid, good estimates of haplotype frequencies must be used in the analysis.

Handling Marker-Marker Linkage Disequilibrium: Pedigree Analysis with Clustered Markers

“…This is an important advance, but we expect that low-cost, rapid SNP genotyping will not only facilitate traditional analysis of human pedigrees but also enable new gene-mapping approaches. For example, genomewide association scans are now within reach (Abecasis et al 2005), and promising new gene-mapping approaches that use pedigree data to model LD between genotyped markers and unobserved disease alleles are being developed (Cantor et al 2005;Li et al 2005).…”

Handling Marker-Marker Linkage Disequilibrium: Pedigree Analysis with Clustered Markers

“…This is an important advance, but we expect that low-cost, rapid SNP genotyping will not only facilitate traditional analysis of human pedigrees but also enable new gene-mapping approaches. For example, genomewide association scans are now within reach (Abecasis et al 2005), and promising new gene-mapping approaches that use pedigree data to model LD between genotyped markers and unobserved disease alleles are being developed (Cantor et al 2005;Li et al 2005).…”

Bayesian Quantitative Trait Locus Mapping Based on Reconstruction of Recent Genetic Histories

“…However, a stepwise strategy, where linkage analysis is carried out first, and then association analysis is employed conditionally on the results of the preliminary linkage analysis, is possible, especially in population isolates. Such a strategy is also the motivation behind the methods that detect associations in the presence of linkage signals (Cantor et al 2005). It could also be possible to treat several tightly linked SNPs as a single multiallelic locus, if credible haplotype information were available.…”

Design and Analysis of Genetic Association Studies to Finely Map a Locus Identified by Linkage Analysis: Assessment of the Extent to Which an Association Can Account for the Linkage

“…Li et al (2005) developed a likelihood method for estimation of haplotype frequencies for a marker and a putative biallelic susceptibility locus. Although the method was initially described for affected sibling pairs, it has recently been extended to include unaffected individuals (Li et al, 2006); a similar method was developed by Cantor et al (2005). These methods test for association in the presence of linkage, and many of them allow for a test of residual linkage conditional on the association, as does the method of Sun et al (2002) for affected sibling pairs.…”

Handling Marker-Marker Linkage Disequilibrium: Pedigree Analysis with Clustered Markers

“…This is an important advance, but we expect that low-cost, rapid SNP genotyping will not only facilitate traditional analysis of human pedigrees but also enable new gene-mapping approaches. For example, genomewide association scans are now within reach (Abecasis et al 2005), and promising new gene-mapping approaches that use pedigree data to model LD between genotyped markers and unobserved disease alleles are being developed (Cantor et al 2005;Li et al 2005).…”

Bayesian Quantitative Trait Locus Mapping Based on Reconstruction of Recent Genetic Histories

“…However, a stepwise strategy, where linkage analysis is carried out first, and then association analysis is employed conditionally on the results of the preliminary linkage analysis, is possible, especially in population isolates. Such a strategy is also the motivation behind the methods that detect associations in the presence of linkage signals (Cantor et al 2005). It could also be possible to treat several tightly linked SNPs as a single multiallelic locus, if credible haplotype information were available.…”

Design and Analysis of Genetic Association Studies to Finely Map a Locus Identified by Linkage Analysis: Assessment of the Extent to Which an Association Can Account for the Linkage

“…Li et al (2005) developed a likelihood method for estimation of haplotype frequencies for a marker and a putative biallelic susceptibility locus. Although the method was initially described for affected sibling pairs, it has recently been extended to include unaffected individuals (Li et al, 2006); a similar method was developed by Cantor et al (2005). These methods test for association in the presence of linkage, and many of them allow for a test of residual linkage conditional on the association, as does the method of Sun et al (2002) for affected sibling pairs.…”

Handling Marker-Marker Linkage Disequilibrium: Pedigree Analysis with Clustered Markers

“…This is an important advance, but we expect that low-cost, rapid SNP genotyping will not only facilitate traditional analysis of human pedigrees but also enable new gene-mapping approaches. For example, genomewide association scans are now within reach (Abecasis et al 2005), and promising new gene-mapping approaches that use pedigree data to model LD between genotyped markers and unobserved disease alleles are being developed (Cantor et al 2005;Li et al 2005).…”

Bayesian Quantitative Trait Locus Mapping Based on Reconstruction of Recent Genetic Histories

“…However, a stepwise strategy, where linkage analysis is carried out first, and then association analysis is employed conditionally on the results of the preliminary linkage analysis, is possible, especially in population isolates. Such a strategy is also the motivation behind the methods that detect associations in the presence of linkage signals (Cantor et al 2005). It could also be possible to treat several tightly linked SNPs as a single multiallelic locus, if credible haplotype information were available.…”

Design and Analysis of Genetic Association Studies to Finely Map a Locus Identified by Linkage Analysis: Assessment of the Extent to Which an Association Can Account for the Linkage

“…Li et al (2005) developed a likelihood method for estimation of haplotype frequencies for a marker and a putative biallelic susceptibility locus. Although the method was initially described for affected sibling pairs, it has recently been extended to include unaffected individuals (Li et al, 2006); a similar method was developed by Cantor et al (2005). These methods test for association in the presence of linkage, and many of them allow for a test of residual linkage conditional on the association, as does the method of Sun et al (2002) for affected sibling pairs.…”